1. Field of the Invention
The present invention relates to methods for producing an indole derivative, and more particularly to a method for producing a rhamnosylated indolocarbazole compound or an indole-3-carboxaldehyde analog.
2. Description of Related Art
The family of indolocarbazole natural products has been a valuable source of lead compounds with potential therapeutic applications in the treatment of cancer and neurodegenerative disorders. In the indolocarbazole family, lestaurtinib has been approved by FDA for treating acute leukemia, CEP-1347 has entered the phase III clinical trial for treating Parkinson's disease, and K-252a, K-252b and staurosporine display anticancer activities. In addition, it is known that K-252d, rhamnosyl-K252c, is capable of inhibiting activity of protein kinase C (PKC). The PKC family plays an important role in cellular proliferation and signal transduction. Hence, specific inhibitors against PKC are promising antitumor drugs for cancer chemotherapy.
S. Nakanishi et al. disclosed the extraction of K-252d from incubation medium of a microorganism. (J. Antibiot., 1986, 39, 1066-1071) However, such extraction needs three purification steps to obtain only 13.3 mg of K-252d from 8.4 L culture medium.
The synthesis of K-252d is summarized in the following Scheme I.

As shown in Scheme I, synthesis of TDP-rhamnose is accomplished by tandem enzymatic conversion of TDP-glucose with NDP-glucose 4,6-dehydratase (Gdh), NDP-4-keto-6-deoxyglucose epimerase (Epi) and NDP-4-ketorhamnose reductase (Kre). Then, TDP-rhamnose is linked to K-252c by N-glycosyltransferase to form K-252d.
Chen et al. disclosed in vitro biosynthesis of TDP-rhamnose. (J. Biol. Chem., 2009, 284, 7352-7363) However, this method needs to purify three enzymes, Gdh, Epi and Kre, and several processing steps.
In addition, it is known that indole-3-carboxaldehyde (ICA) has anti-bacterial activity to gram positive bacteria such as S. aureus or to gram negative bacteria such as E. coli or E. faecium. Further, ICA can be modified for treating stroke, cancer or neurodegeneration disease such as Parkinson's disease. A modified ICA, 3-ICA-TSC, is an amebacide.
However, it is very complicated to purify ICA from a microorganism. (Nat. Prod. Res., 2005, 19, 645-652) S. S. Panda et al. disclosed chemical synthesis of ICA, which may cause environmental problems due to usage of organic solvents and toxic agents. (Indian J. Pharm. Sci., 2008, 70, 208-215)
Therefore, in order to overcome the drawbacks of the conventional methods, the present invention provide a novel method for in vitro simply and efficiently producing an indole derivative.